1. Field of the Invention
The present invention relates to development of cancer drug, in particular, the development of novel anthra[1,2-d]imidazole-6,11-dione derivatives, preparation method and application thereof.
2. Description of the Prior Art
Telomere
A telomere is a region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from deterioration, recombination, and end-to-end fusion. A telomere is composed of short and repeated DNA sequences. A high percentage of guanine (G) is present in this DNA sequence from the 5′-end to the 3′-end. The telomere DNA sequence (TTAGGG)n is conserved among vertebrates, including humans.
In a normal somatic cell, the terminal end of the chromosome will lose a part of the RNA primer after each replication, and will shorten off about 50-60 bp after each cell division. When the telomere is shortened to a certain extent, the cell will go to apoptosis. This phenomenon is called an end-replication problem of a cell.
Telomerase
Telomerase is the enzyme that synthesizes telomeric DNA, the terminal DNA at chromosome ends which, together with telomere-binding proteins, confers stability to chromosomes. In most organisms, replication and maintenance of the length of telomere has to rely on telomerase. The telomerase is composed of RNA and protein subunits. At present, part of the important telomerase subunits have been identified. The composition of human telomerase comprises human telomerase reverse transcriptase (hTERT) having reverse transciptase activity, human telomerase RNA component used as a template, and some telomere-binding proteins such as human telomerase-associated protein, p23, hsp90, hsp40, hsp70 and the like.
Many research studies have indicated that the activity of human telomerase can only be detected in cells having a high proliferation ability, for example, germ cells, hemopoietic cells, part of stem cells, most of immortalized cells and most of tumor cells. In the somatic cell, the telomere will be shortened gradually as the number of cell divisions increase, which may be considered as the mitotic clock for counting the number of cell divisions. When a telomere is shortened to a certain extent, the cell will stop division and entering an aging stage, stay at this stage for a period of time, and then go to death. This period of time is called mortality stage 1 (M1 stage). When a tumor suppressor gene such as p53 or Rb is mutated within the M1 stage, the cell might escape from the aging stage and continue cell division in a period of time which is called mortality stage 2 (M2 stage). If a cell lacks telomerase activity during this period, the length of a telomere will be reduced further, and the telomere will not be able to protect the terminal end of the chromosome. This might result into the instability of the chromosome, as well as the cell cannot transfer genetic information completely and enters apoptosis in the end. Therefore, the M2 stage is also called a crisis stage. Most of cells will die in the M2 stage, except a small part of cells with telomerase activity will survive. This small part of cells will continue to divide without limitation and become an immortalized cell (or a cancer cell).
In view of the foregoing, it is thought generally that the activation of telomerase can maintain the length of a telomere so as to prevent a cell from entering the aging stage; or the inhibition of telomerase activity can be used to limit the division of a cancer cell. Both thoughts may become key factors in the development of a cell toward immortalization or cancerization. In summary, using telomerase inhibitors to treat cancer have been considered as a novel cancer-specific therapy, as most tumor cells have high expression of telomerase, whereas most normal somatic cells express low or undetectable levels of telomerase and are therefore an attractive target for the design of anticancer agents.
Anthraquinone-containing extracts from different plant sources such as senna, cascara, aloe, frangula, and rhubarb have been found to have wide variety of pharmacological activities such as anti-inflammatory, wound healing, analgesic, antipyretic, antimicrobial, and antitumor activities. Some of the anthraquinone derivatives have also shown antitumor activity. Therefore, many investigators consider them as highly promising lead candidates in drug design.
In view of the importance of the development of cancer therapy drugs, the invention provides inventive anthra[1,2-d]imidazole-6,11-dione derivatives, preparation method and application thereof.